Journal Article

Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K–Akt/NF-κB pathway by lysophosphatidic acid, an ovarian cancer-activating factor

Chia-Hung Chou, Lin-Hung Wei, Min-Liang Kuo, Yun-Ju Huang, Kuo-Pao Lai, Chi-An Chen and Chang-Yao Hsieh

in Carcinogenesis

Volume 26, issue 1, pages 45-52
Published in print January 2005 | ISSN: 0143-3334
Published online January 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh301
Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K–Akt/NF-κB pathway by lysophosphatidic acid, an ovarian cancer-activating factor

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Bioactive lysophospholipid, lysophosphatidic acid (LPA), is consistently raised in the ascites of patients with ovarian cancer. Interleukin-6 (IL-6) is a pleiotropic cytokine, which is assumed to be involved in ovarian carcinogenesis. However, the regulation of IL-6 in ovarian cancer remains largely unknown. To elucidate the pathogenesis of ovarian cancer, this study investigated how LPA affects IL-6 production in ovarian cancer cells. Experimental results indicated that LPA stimulates IL-6 expression in all ovarian cancer cell lines tested, but not in normal ovarian surface epithelial (NOSE) cells, owing to the lack of LPA-specific Edg4 and/or Edg7 receptors in NOSE cells. This work demonstrated that LPA transcriptionally activates IL-6 expression, which can be totally blocked by the pertussis toxin, indicating that Gi-mediated signaling is critically involved in inducing IL-6 by LPA. Pharmacological and genetic inhibition assays revealed that Gi-mediated PI3K activation phosphorylated downstream Akt and subsequently induced NF-κB activation causes the induction of IL-6 by LPA in SK-OV-3 cells. In summary, data presented here demonstrate that LPA is an important inducer of IL-6 and LPA-regulated IL-6 expression via a Gi/PI3K–Akt/NF-κB pathway in ovarian cancer cells, providing molecular therapeutic targets for treating ovarian cancer.

Keywords: dn, dominant negative; EIA, enzyme immunoassay; HUVECs, human umbilical veins endothelial cells; IL-6, interleukin-6; LPA, lysophosphatidic acid; NOSE, normal ovarian surface epithelial; ODN, oligodeoxynucleotides; PDTC, 1-pyrrollidinecarbodithioic acid; PTX, pertussis toxin

Journal Article.  5569 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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